title: Effects of ubiquilin 1 on the unfolded protein response.
abstract: Previous studies have implicated the unfolded protein response (UPR) in the pathogenesis of Alzheimer's disease (AD). We previously reported that DNA variants in the ubiquilin 1 (UBQLN1) gene increase the risk for AD. Since UBQLN1 has been shown to play a role in the UPR, we assessed the effects of overexpression and downregulation of UBQLN1 splice variants during tunicamycin-induced ER stress. In addition to previously described transcript variants, TV1 and TV2, we identified two novel transcript variants of UBQLN1 in brain: TV3 (lacking exons 2-4) and TV4 (lacking exon 4). Overexpression of TV1-3, but not TV4 significantly decreased the mRNA induction of UPR-inducible genes, C/EBP homologous protein (CHOP), BiP/GRP78, and protein disulfide isomerase (PDI) during the UPR. Stable overexpression of TV1-3, but not TV4, also significantly decreased the induction of CHOP protein and increased cell viability during the UPR. In contrast, downregulation of UBQLN1 did not affect CHOP mRNA induction, but instead increased PDI mRNA levels. These findings suggest that overexpression UBQLN1 transcript variants TV1-3, but not TV4, exert a protective effect during the UPR by attenuating CHOP induction and potentially increasing cell viability.
authors.affiliation: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, 02129-4404, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Lu
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.forename: Donna M
authors.initials: DM
authors.lastname: Romano
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D017510:Protein Folding; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; C107792:UBQLN1 protein, human; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D053148:Caspase 3; D019704:Protein Disulfide-Isomerases